Lyme disease is the most common vector borne disease in the United States. Although antibiotic therapy is clinically effective in treating the symptoms of Lyme disease for patients early in the course of disease, a significant number of patients who receive delayed therapy report persistent symptoms. The cause of persistent symptoms in patients after antibiotic therapy for Lyme disease remains highly controversial. Theories include persistence of infection, induction of autoimmune responses and non-healing tissue damage. There is currently no available test to document resolution of infection and clearance of the organism, Borrelia burgdorferi. Although the prevailing belief in the scientific community has been that bacteria are completely cleared after antibiotic therapy, recent studies in mice and dogs have shown that bacteria can persist after treatment and are detectable by PCR or xenodiagnosis (the feeding of uninfected Ixodes ticks on the treated animals). We have recently performed a pilot trial of xenodiagnosis in humans. We found that xenodiagnosis is safe and can detect B. burgdorferi in some patients after antibiotic therapy. Here we propose the Phase II study to determine whether a detection of bacteria by xenodiagnosis correlates with prolonged symptoms in patients after infection with B. burgdorferi. In specific aim #1, we will enroll subjects who have the characteristic erythema migrans (EM) rash after completion of antibiotic therapy. Changes in the subjects functional capacity over time will be determined by serial testing using the Short Form 36 version 2 (SF-36v2) and the Fatigue Severity Scale (FSS). Patients will have xenodiagnosis performed at 2-4 months after treatment and again at 8-10 months after treatment. Recovered ticks will be tested for the presence of bacteria using multiple technologies including culture, PCR, fluorescent microscopy and mass spectroscopy. Because only a minority of subjects in Aim 1 are likely to have persistent symptoms, in Aim 2 we will specifically target subjects with persistent symptoms. We will enroll subjects with persistent symptoms associated with Lyme greater than 6 months after their original treatment. Functional status will be measured by SF-36v2 and FSS and xenodiagnosis will be performed as in Aim 1. Results of xenodiagnosis in asymptomatic patients at the 8-10 month time point from Aim 1 will serve as the comparison group for the subjects in Aim 2. These studies have the potential to address the controversial issue of whether bacterial persistence is linked to prolonged symptoms in patients who have been treated for Lyme disease. Identifying the link between persistent infections and persistent symptoms is important because it may directly impact strategies that are used to treat chronic Lyme disease.